The Microbiome and p-Inulin in Hemodialysis: A Feasibility Study.
crossover trial
dialysis
feasibility studies
hemodialysis
microbiome
p-inulin
prebiotic
Journal
Kidney360
ISSN: 2641-7650
Titre abrégé: Kidney360
Pays: United States
ID NLM: 101766381
Informations de publication
Date de publication:
25 03 2021
25 03 2021
Historique:
received:
13
10
2020
accepted:
14
01
2021
entrez:
4
4
2022
pubmed:
15
1
2021
medline:
8
4
2022
Statut:
epublish
Résumé
The intestinal microbiome is an appealing target for interventions in ESKD because of its likely contribution to uremic toxicity. Before conducting clinical trials of microbiome-altering treatments, it is necessary to understand the within-person and between-person variability in the composition and function of the gut microbiome in patients with ESKD. We conducted a multicenter, nonrandomized, crossover feasibility study of patients on maintenance hemodialysis consisting of three phases: pretreatment (8 weeks); treatment, during which the prebiotic, p-inulin, was administered at a dosage of 8 g twice daily (12 weeks); and post-treatment (8 weeks). Stool samples were collected 1-2 times per week and blood was collected weekly for 28 weeks. The gut microbiome was characterized using 16S ribosomal-RNA sequencing and metabolomic profiling. A total of 11 of the 13 participants completed the 28-week study. Interparticipant variability was greater than intraparticipant variability for microbiome composition ( The intraparticipant stability of the gut microbiome under no-treatment conditions, the tolerability of p-inulin, the signals of increased diversity of the microbiome with p-inulin treatment, and the willingness of participants to provide stool samples all support the feasibility of a larger trial to investigate interventions targeting the gut microbiome in patients with ESKD. Whether or not p-inulin has sufficient efficacy as an intervention requires evaluation in larger studies. Gut Microbiome and p-Inulin in Hemodialysis, NCT02572882.
Sections du résumé
Background
The intestinal microbiome is an appealing target for interventions in ESKD because of its likely contribution to uremic toxicity. Before conducting clinical trials of microbiome-altering treatments, it is necessary to understand the within-person and between-person variability in the composition and function of the gut microbiome in patients with ESKD.
Methods
We conducted a multicenter, nonrandomized, crossover feasibility study of patients on maintenance hemodialysis consisting of three phases: pretreatment (8 weeks); treatment, during which the prebiotic, p-inulin, was administered at a dosage of 8 g twice daily (12 weeks); and post-treatment (8 weeks). Stool samples were collected 1-2 times per week and blood was collected weekly for 28 weeks. The gut microbiome was characterized using 16S ribosomal-RNA sequencing and metabolomic profiling.
Results
A total of 11 of the 13 participants completed the 28-week study. Interparticipant variability was greater than intraparticipant variability for microbiome composition (
Conclusions
The intraparticipant stability of the gut microbiome under no-treatment conditions, the tolerability of p-inulin, the signals of increased diversity of the microbiome with p-inulin treatment, and the willingness of participants to provide stool samples all support the feasibility of a larger trial to investigate interventions targeting the gut microbiome in patients with ESKD. Whether or not p-inulin has sufficient efficacy as an intervention requires evaluation in larger studies.
Clinical Trial registry name and registration number
Gut Microbiome and p-Inulin in Hemodialysis, NCT02572882.
Identifiants
pubmed: 35369018
doi: 10.34067/KID.0006132020
pii: 02200512-202103000-00008
pmc: PMC8786005
doi:
Substances chimiques
Inulin
9005-80-5
Banques de données
ClinicalTrials.gov
['NCT02572882']
Types de publication
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
445-455Subventions
Organisme : NIDDK NIH HHS
ID : U01 DK099919
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK099923
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK099914
Pays : United States
Organisme : NIDDK NIH HHS
ID : R21 DK100772
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK096189
Pays : United States
Investigateurs
Alan Kliger
(A)
David M Charytan
(DM)
Emily Robinson
(E)
Mark Williams
(M)
Daniel E Weiner
(DE)
Finnian Mc Causland
(F)
Sushrut Waikar
(S)
Ezra Aurien-Blajeni
(E)
Angeles Cinelli
(A)
Tayyaba Nisam
(T)
Sookyung Rim
(S)
Paul Seok
(P)
Caroline Smith
(C)
Jasmine Rollins
(J)
Dominic Raj
(D)
Renu Regunathan-Shenk
(R)
Shailendra Sharma
(S)
Ali Ramezani
(A)
Sarah Andrews
(S)
Michelle Dumadag
(M)
Christina Franco
(C)
Maria Wing
(M)
Jonathan Himmelfarb
(J)
Rajnish Mehrotra
(R)
Lisa Anderson
(L)
Lori Linke
(L)
Linda Manahan
(L)
T Alp Ikizler
(TA)
Adriana Hung
(A)
Kerri Cavanaugh
(K)
Cindy Booker
(C)
Brigitte Brannon
(B)
Adrienne Clagett
(A)
Charles Ellis
(C)
Laura M Dember
(LM)
J Richard Landis
(JR)
Amanda Anderson
(A)
Jesse Hsu
(J)
Denise Cifelli
(D)
Shawn Ballard
(S)
Marie Durborow
(M)
Tamara Howard
(T)
Natalie Kuzla
(N)
Lisa Nessel
(L)
Ann Tierney
(A)
Hicham Skali
(H)
Scott Solomon
(S)
Aria Rad
(A)
Marcelo Di Carli
(M)
Masha Gaber
(M)
Courtney Foster
(C)
Paul Kimmel
(P)
John Kusek
(J)
Kevin Abbott
(K)
Paul Palevsky
(P)
Stuart Goldstein
(S)
Patricia Hibberd
(P)
George Kaysen
(G)
Joshua Korzenik
(J)
Joao Lima
(J)
Allen Nissenson
(A)
Vasan Ramachandran
(V)
David Raboussin
(D)
Jeffrey Siegel
(J)
Nosratola Vaziri
(N)
Gloria Vigliani
(G)
Janet Wittes
(J)
Informations de copyright
Copyright © 2021 by the American Society of Nephrology.
Déclaration de conflit d'intérêts
D.M. Charytan reports receiving personal fees from AstraZeneca, Douglas and London, Fresenius, GSK, Merck, PLC Medical, and Zoll; grants and personal fees from Amgen, Gilead, Medtronic, and NovoNordisk; grants from Bioporto; other from Daichi-Sankyo; and personal fees and other from Janssen, outside the submitted work. L.M. Dember receives consulting fees from GlaxoSmithKline and Merck, and compensation from the National Kidney Foundation for her role as deputy editor of American Journal of Kidney Diseases, outside of the submitted work. J. Himmelfarb reports being a founder of AKTIV-X Technologies, Inc., with equity; and has received fees for acting as a consultant or scientific advisory board member for Akebia, Chinook Therapeutics, Maze Therapeutics, Pfizer, Renalytix AI, and Seattle Genetics. T.A. Ikizler received personal fees from Abbott Renal Care and Fresenius Kabi, during the conduct of the study. P.L. Kimmel is a coeditor of Chronic Renal Disease (Academic Press, San Diego, CA), and a member of the board of directors of the Washington Academy of Medicine. A.S. Kliger receives income from the American Society of Nephrology, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and Yale New Haven Hospital. H. Li receives consulting fees from Eli Lily, outside the submitted work. R. Mehrotra receives consulting fees from Baxter Healthcare, outside the submitted work. All remaining authors have nothing to disclose.
Références
Ramezani A, Massy ZA, Meijers B, Evenepoel P, Vanholder R, Raj DS: Role of the gut microbiome in uremia: A potential therapeutic target. Am J Kidney Dis 67: 483–498, 2016 https://doi.org/10.1053/j.ajkd.2015.09.027
doi: 10.1053/j.ajkd.2015.09.027
Sekirov I, Russell SL, Antunes LC, Finlay BB: Gut microbiota in health and disease. Physiol Rev 90: 859–904, 2010 https://doi.org/10.1152/physrev.00045.2009
doi: 10.1152/physrev.00045.2009
Wu MJ, Chang CS, Cheng CH, Chen CH, Lee WC, Hsu YH, Shu KH, Tang MJ: Colonic transit time in long-term dialysis patients. Am J Kidney Dis 44: 322–327, 2004 https://doi.org/10.1053/j.ajkd.2004.04.048
doi: 10.1053/j.ajkd.2004.04.048
Kalantar-Zadeh K, Kopple JD, Deepak S, Block D, Block G: Food intake characteristics of hemodialysis patients as obtained by food frequency questionnaire. J Ren Nutr 12: 17–31, 2002 https://doi.org/10.1053/jren.2002.29598
doi: 10.1053/jren.2002.29598
Dethlefsen L, Relman DA: Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A 108[Suppl 1]: 4554–4561, 2011 https://doi.org/10.1073/pnas.1000087107
doi: 10.1073/pnas.1000087107
Vaziri ND, Dure-Smith B, Miller R, Mirahmadi MK: Pathology of gastrointestinal tract in chronic hemodialysis patients: An autopsy study of 78 cases. Am J Gastroenterol 80: 608–611, 1985
Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L, Canani RB, Flint HJ, Salminen S, Calder PC, Sanders ME: Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 11: 506–514, 2014 https://doi.org/10.1038/nrgastro.2014.66
doi: 10.1038/nrgastro.2014.66
Paul R, Raj DS: Metabolic synergy to uremic toxicity: A tale of symbiosis and dysbiosis in CKD. NephSAP 18: 199–207, 2019 https://doi.org/10.1681/nsap.2019.18.4.1
doi: 10.1681/nsap.2019.18.4.1
Mimee M, Citorik RJ, Lu TK: Microbiome therapeutics – Advances and challenges. Adv Drug Deliv Rev 105: 44–54, 2016
Meijers BK, De Preter V, Verbeke K, Vanrenterghem Y, Evenepoel P: p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin. Nephrol Dial Transplant 25: 219–224, 2010 https://doi.org/10.1093/ndt/gfp414
doi: 10.1093/ndt/gfp414
NutritionQuest: Our Research: Questionnaires. Available at: https://nutritionquest.com/company/our-research-questionnaires/ . Accessed July 5, 2020
Revicki DA, Wood M, Wiklund I, Crawley J: Reliability and validity of the Gastrointestinal Symptom Rating Scale in patients with gastroesophageal reflux disease. Qual Life Res 7: 75–83, 1998 https://doi.org/10.1023/A:1008841022998
doi: 10.1023/A:1008841022998
Barupal DK, Zhang Y, Shen T, Fan S, Roberts BS, Fitzgerald P, Wancewicz B, Valdiviez L, Wohlgemuth G, Byram G, Choy YY, Haffner B, Showalter MR, Vaniya A, Bloszies CS, Folz JS, Kind T, Flenniken AM, McKerlie C, Nutter LMJ, Lloyd KC, Fiehn O: A comprehensive plasma metabolomics dataset for a cohort of mouse knockouts within the international mouse phenotyping Consortium. Metabolites 9: 101, 2019 https://doi.org/10.3390/metabo9050101
doi: 10.3390/metabo9050101
Gao B, Lue HW, Podolak J, Fan S, Zhang Y, Serawat A, Alumkal JJ, Fiehn O, Thomas GV: Multi-omics analyses detail metabolic reprogramming in lipids, carnitines, and use of glycolytic intermediates between prostate small cell neuroendocrine carcinoma and prostate adenocarcinoma. Metabolites 9: 82, 2019 https://doi.org/10.3390/metabo9050082
doi: 10.3390/metabo9050082
Fiehn O: Metabolomics by gas chromatography-mass spectrometry: Combined targeted and untargeted profiling. Curr Protoc Mol Biol 114: 30.4.1–30.4.32, 2016
Tsugawa H, Cajka T, Kind T, Ma Y, Higgins B, Ikeda K, Kanazawa M, VanderGheynst J, Fiehn O, Arita M: MS-DIAL: Data-independent MS/MS deconvolution for comprehensive metabolome analysis. Nat Methods 12: 523–526, 2015 https://doi.org/10.1038/nmeth.3393
doi: 10.1038/nmeth.3393
Edgington E: Approximate randomization tests. J Psychol 72: 143–149, 1969 https://doi.org/10.1080/00223980.1969.10543491
doi: 10.1080/00223980.1969.10543491
Pinheiro JC, Bates DM: Mixed-Effects Models in S and S-PLUS, New York, Springer-Verlag New York, Inc., 2000 https://doi.org/10.1007/978-1-4419-0318-1
R Core Team: R: A language and environment for statistical computing. Available at: https://www R-project org/ . Accessed November 18, 2020
Chen J, Bittinger K, Charlson ES, Hoffmann C, Lewis J, Wu GD, Collman RG, Bushman FD, Li H: Associating microbiome composition with environmental covariates using generalized UniFrac distances. Bioinformatics 28: 2106–2113, 2012 https://doi.org/10.1093/bioinformatics/bts342
doi: 10.1093/bioinformatics/bts342
Benjamini Y, Hochberg Y: Controlling the false discovery rate: A practical and powerful approach to multiple testing. J R Stat Soc Series B-Methodol 57: 289–300, 1995 https://doi.org/10.1111/j.2517-6161.1995.tb02031.x
doi: 10.1111/j.2517-6161.1995.tb02031.x
Kelly BJ, Gross R, Bittinger K, Sherrill-Mix S, Lewis JD, Collman RG, Bushman FD, Li H: Power and sample-size estimation for microbiome studies using pairwise distances and PERMANOVA. Bioinformatics 31: 2461–2468, 2015 https://doi.org/10.1093/bioinformatics/btv183
doi: 10.1093/bioinformatics/btv183
Joossens M, Faust K, Gryp T, Nguyen ATL, Wang J, Eloot S, Schepers E, Dhondt A, Pletinck A, Vieira-Silva S, Falony G, Vaneechoutte M, Vanholder R, Van Biesen W, Huys GRB, Raes J, Glorieux G: Gut microbiota dynamics and uraemic toxins: One size does not fit all. Gut 68: 2257–2260, 2019 https://doi.org/10.1136/gutjnl-2018-317561
doi: 10.1136/gutjnl-2018-317561
Eloot S, Van Biesen W, Roels S, Delrue W, Schepers E, Dhondt A, Vanholder R, Glorieux G: Spontaneous variability of pre-dialysis concentrations of uremic toxins over time in stable hemodialysis patients. PLoS One 12: e0186010, 2017 https://doi.org/10.1371/journal.pone.0186010
doi: 10.1371/journal.pone.0186010
Sommer F, Anderson JM, Bharti R, Raes J, Rosenstiel P: The resilience of the intestinal microbiota influences health and disease. Nat Rev Microbiol 15: 630–638, 2017 https://doi.org/10.1038/nrmicro.2017.58
doi: 10.1038/nrmicro.2017.58
Rossi M, Johnson DW, Morrison M, Pascoe EM, Coombes JS, Forbes JM, Szeto CC, McWhinney BC, Ungerer JP, Campbell KL: Synbiotics easing renal failure by improving gut microbiology (SYNERGY): A randomized trial. Clin J Am Soc Nephrol 11: 223–231, 2016 https://doi.org/10.2215/CJN.05240515
doi: 10.2215/CJN.05240515
Li L, Xiong Q, Zhao J, Lin X, He S, Wu N, Yao Y, Liang W, Zuo X, Ying C: Inulin-type fructan intervention restricts the increase in gut microbiome-generated indole in patients with peritoneal dialysis: A randomized crossover study. Am J Clin Nutr 111: 1087–1099, 2020 https://doi.org/10.1093/ajcn/nqz337
doi: 10.1093/ajcn/nqz337
Chinda D, Nakaji S, Fukuda S, Sakamoto J, Shimoyama T, Nakamura T, Fujisawa T, Terada A, Sugawara K: The fermentation of different dietary fibers is associated with fecal clostridia levels in men. J Nutr 134: 1881–1886, 2004 https://doi.org/10.1093/jn/134.8.1881
doi: 10.1093/jn/134.8.1881
Bammens B, Evenepoel P, Keuleers H, Verbeke K, Vanrenterghem Y: Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients. Kidney Int 69: 1081–1087, 2006 https://doi.org/10.1038/sj.ki.5000115
doi: 10.1038/sj.ki.5000115
Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar M, Choukroun G, Vanholder R, Massy ZA; European Uremic Toxin Work Group (EUTox): Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 4: 1551–1558, 2009 https://doi.org/10.2215/CJN.03980609
doi: 10.2215/CJN.03980609
Tang WH, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B, Li XS, Levison BS, Hazen SL: Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 116: 448–455, 2015 https://doi.org/10.1161/CIRCRESAHA.116.305360
doi: 10.1161/CIRCRESAHA.116.305360
Khosroshahi HT, Abedi B, Ghojazadeh M, Samadi A, Jouyban A: Effects of fermentable high fiber diet supplementation on gut derived and conventional nitrogenous product in patients on maintenance hemodialysis: A randomized controlled trial. Nutr Metab (Lond) 16: 18, 2019 https://doi.org/10.1186/s12986-019-0343-x
doi: 10.1186/s12986-019-0343-x
Poesen R, Evenepoel P, de Loor H, Delcour JA, Courtin CM, Kuypers D, Augustijns P, Verbeke K, Meijers B: The influence of prebiotic arabinoxylan oligosaccharides on microbiota derived uremic retention solutes in patients with chronic kidney disease: A randomized controlled trial. PLoS One 11: e0153893, 2016 https://doi.org/10.1371/journal.pone.0153893
doi: 10.1371/journal.pone.0153893
Fujisaka S, Avila-Pacheco J, Soto M, Kostic A, Dreyfuss JM, Pan H, Ussar S, Altindis E, Li N, Bry L, Clish CB, Kahn CR: Diet, genetics, and the gut microbiome drive dynamic changes in plasma metabolites. Cell Rep 22: 3072–3086, 2018 https://doi.org/10.1016/j.celrep.2018.02.060
doi: 10.1016/j.celrep.2018.02.060
Zhang Y, Guo S, Xie C, Fang J: Uridine metabolism and its role in glucose, lipid, and amino acid homeostasis. BioMed Res Int 2020: 7091718, 2020